Myeloma is an incurable malignancy, and excessive bone destruction is a major cause of morbidity in myeloma patients. However, the biologic mechanisms involved in the pathogenesis of myeloma-induced bone disease are poorly understood. Heparanase, an enzyme that cleaves the heparan sulfate chains of proteoglycans, is upregulated in a variety of human tumors, including myeloma. I have previously demonstrated that heparanase promotes robust myeloma tumor growth and supports spontaneous metastasis to bone. In addition, I have recently made the striking discovery that the expression of heparanase by myeloma tumor cells is a major determinant of the osteolytic phenotype where it potently promotes both local and systemic osteolysis. The goal of this project is to determine how heparanase promotes myeloma-induced bone disease and to determine the potential of heparanase inhibition for the treatment of myeloma bone disease. The formation and function of bone resorbing osteoclasts is activated by Receptor Activator of NF-?B Ligand (RANKL) and inhibited by osteoprotegerin (OPG). Activated osteoclasts secrete matrix metalloproteinase-9 (MMP-9), degrading bone tissue. I and my colleagues have found, for the first time, that heparanase significantly elevates the expression of RANKL, MMP-9, and transcription factor Runx2 in myeloma cells. In addition, heparanase increases RANKL and decreases OPG expression in osteoblast precursors. Here I hypothesize that heparanase drives myeloma osteolysis by increasing the expression and secretion of RANKL and MMP-9 in myeloma cells via the upregulation of Runx2. I further postulate that heparanase modulates osteoblast precursors to enhance their role as osteoclast- support cells. Thus, myeloma bone disease can be ameliorated by the inhibition of heparanase. To test this novel hypothesis, Aims 1 and 2 will focus on how heparanase promotes myeloma bone destruction by affecting myeloma cells and osteoblasts/stromal cells. Aim 3 will investigate whether inhibiting heparanase can protect bone from myeloma-induced bone disease. This project will determine the role of heparanase in promoting the osteolytic bone destruction characteristic of myeloma and provide further insight into the use of heparanase inhibitors as treatment for myeloma and other osteolytic tumors.